Project Summary The discovery and development of effective chemical therapeutics for human disease is limited by the shortcomings of synthetic chemistry that make investigating important chemical structures difficult. In particular, the clinical potential of many complex polycyclic structures is under-explored due to a lack of methods for their preparation. Bridging this gap will allow many new structures to be synthesized rapidly, leading to an increased rate at which new therapeutics are discovered. The long-term goal of this research program is to make significant contributions to both chemistry and medicine by developing general synthetic strategies for the rapid preparation of biologically active complex polycyclic structures. The specific goals of the proposed research are to establish new strategies for the rapid and stereocontrolled synthesis of a diverse range of pharmacologically relevant polycyclic small-molecules, including natural products and synthetic natural product-like scaffolds. Our research is focused by two specific aims that seek to provide access to unique and challenging chemotypes through efficient and modular fragment coupling processes. The Specific Aims of the project are: 1. Develop Unified Strategies to Access Stereochemically Challenging Chemotypes ? In this Aim oxidative coupling of simple enone substrates is a central methodological focus. 2. Develop Catalytic Fragment Couplings for Accessing Diverse Ring Systems ? in this Aim a series of new Brnsted acid catalyzed reactions are put forth. The proposed research is innovative because it will utilize general reactions to access a wide range of challenging molecules with different structures from readily prepared and structurally simple building blocks. The expected outcomes of this research will be the concise synthesis of many medicinally important structures that are challenging to current methods. This proposed research is significant for human health because it is expected to provide underexplored complex polycyclic structures in quantities that will ensure their utilization in discovering new chemical therapeutics.